This proposal seeks to consolidate existing/pending grant support into a single grant, as defined by guidelines for the National Cancer Institute Outstanding Investigator Grant. Activities under the award would include continuing investigation of the bleomycin group antibiotics, development of novel strategies for the manipulation (principally strand scission) of nucleic acids under conditions that can obtain in intact cells, and the utilization of misacylated tRNA's to elaborate "synthetic enzymes" for study. These enzymes will be key target enzymes for cancer chemotherapy (eg, dihydrofolate reductase) that contain synthetic amino acids at predetermined positions capable of facilitating precise analysis of the underlying chemistry of enzyme function, and hence can guide the synthesis of improved enzyme inhibitors that are of interest as antitumor agents.